Bicyclic pyrimidines



United States Patent Oflice 3,454,573 Patented July 8, 1969 3,454,573 BICYCLIC PYRIMIDINES Richard William James Carney, Murray Hill, Herbert Morton Blatter, Irvington, and George de Stevens, Woodland Park, Summit, N.J., assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Continuation-in-part of application Ser. No. 427,151, Jan. 21, 1965, which is a continuation-in-part of application Ser. No. 351,200, Mar. 11, 1964, now abandoned. This application Sept. 17, 1965, Ser. No.

Int. Cl. C07d 51/46; A61k 27/00 US. Cl. 260-251 2 Claims ABSTRACT OF THE DISCLOSURE Bicyclic pyrimidines of the formula A=alkylene or alkenylene R =aliphatic or aromatic radical R =an imino, O, S or substituted CH group corresponding aromatic quaternaries and salts thereof are antimicrobial, anthelmintic and antiinflammatory agents.

in which A stands for a divalent saturated or unsaturated aliphatic radical having from three to five carbon atoms as ring members and at most one double bond, each of the groups R and R for an aliphatic or aromatic radical, R for an imino group, R for an amino group, an aliphatically substituted hydroxy or mercapto group or an N-substituted azacyclic arylidenemethyl group in which the ring-nitrogen is part of an enamine grouping and A11 for the anion of an acid or the hydroxyl ion.

A divalent aliphatic radical representing the group A preferably stands for a lower alkylene or alkenylene radical having at least three carbon atoms, such as 1,3- propylene, 1,4-butylene, 2,2-dimethyl-1,4-butylene, 1,4- or 1,5-pentylene; 1,3-prop-l-enylene, 1,4-but-l-enylene, 1,4-but-2-enylene or 1,5-pent-1-enylene. These aliphatic radicals are preferably unsubstituted but may be substituted by one or more than one substituent located in any position available for substitution, such as etherified hydroxy, for example lower alkoxy, such as methoxy, ethoxy, nor i-propoxy or n-butoxy, esterified hydroxy, for example halogeno, such as fluoro, chloro or bromo, trifluoromethyl, etherified mercapto, for example lower alkylmercapto, such as methylor ethylmercapto, nitro, disubstituted amino, for example, di-lower alkyl-amino, such as dimethylamino or diethylamino, as well as oxo or thiono.

An aliphatic radical representing R and R is especially an alkyl radical having up to twelve carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, npentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl or nundecyl. It may also be an alkenyl radical having up to twelve carbon atoms, such as allyl or undecenyl, a cycloaliphatic or cycloaliphaticaliphatic radical, such as cycloalkyl or cycloalkyl-lower alkyl having from three to eight, especially from five to seven, ring members, e.g. cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, cyclopropylmethyl, cycloypentylmethyl, 2- cyclopentylet hyl, cyclohexylmethyl, l-cyclohexylethyl or cycloheptylmethyl, an araliphatic radical, such as monocyclic carbocyclic aryl-lower alkyl, e.g. benzyl, l-phenylethyl or Z-phenylethyl.

An aromatic radical representing R and R is particularly a monocyclic carbocyclic aryl radical, e.g. phenyl or substituted phenyl. It may also be a bicyclic carbocyclic aryl radical, i.e. naphthyl or substituted naphthyl, or a heterocyclic, particularly monocyclic aryl radical, such as pyridyl, thienyl or furyl.

Said radicals R and R may be unsubstituted or may have one or more than one of the same or difierent substituents attached to any position available for substitution, especially in the aromatic portion. They are, for example, lower alkyl, e.g. methyl, ethyl, n-propyl or isopropyl, etherified hydroxy, such as lower alkoxy, e.g. methoxy, ethoxy, n-propoxy, isopropoxy or n-butoxy, esterified hydroxy, such as halogeno e.g. fluoro, chloro or bromo, trifluoromethyl, etherified mercapto, such as lower alkylmercapto, e.g. methylmercapto or ethylrnercapto, nitro, disubstituted amino, such as di-lower alkylamino, e.g. dimethylamino or diethylamino, alkyleneimino in which alkylene has from four to six carbon atoms, e.g. pyrrolidino or piperidino, oxo or thiono.

A monoor bicyclic carbocyclic aryl radical, therefore, is primarily phenyl, (lower alkyD-phenyl, (lower alkoxy) phenyl, (halogeno) phenyl, (trifiuoromethyl)- phenyl, (lower alkylmercapto)-phenyl, (nitro)-phenyl, (di-lower alkylamino)-phenyl, 1 naphthyl, 2 -naphthyl, (lower alkyl)-naphthyl, (lower alkoxy)-naphthyl, (halogeno)-naphthyl, (trifiuoromethyl)-naphthyl, (lower alkylmercapto)-naphthyl, (nitro)-naphthyl or (di-lower alkylamino) -n aphthyl.

The aliphatic radicals R and R may also be interrupted by hetero atoms, preferably by one oxygen, sulfur and/or nitrogen atom. Such radicals are, for example, lower alkoxy-lower alkyl groups, such as methoxymethyl, ethoxymethyl, n-propylmethyl, 1- or 2-n1ethoxy-, ethoxy or i-propoXy-ethyl, 1 2- or 3-methoxy-, ethoxy or n-propoxy-propyl or 4-tert. butoxy-butyl, the corresponding phenoxy-lower alkyl and lower alkylmercapto-lower alkyl groups, monoor di-lower alkylamino-lower alkyl, alkyleneimino-lower alkyl or aza, oxaor thia-alkyleneimino-lower alkyl or N-phenyl-aza-alkyleneimino-lower alkyl groups with 4 to 6 ring-carbon atoms and in which latter the hetero-atom is preferably separated from the ring-nitrogen atom by at least two carbon atoms, such alkoxy-lower alkyl, such as carboxymethyl, 2-carboxyethyl, S-dimethylaminoor S-diethylamino-propyl, 2- pyrrolidino-ethyl, 3-piperidino-propyl, Z-piperazino-ethyl, 2-(4-methyl-piperazino)-ethyl, 3 (4 ethyl-piperazino)- propyl, 2-(4-phenyl-piperazino)-ethyl, 2-morpholino-ethyl or 3-thiamorpholino-propyl.

The imino group R, can be unsubstituted, but preferably is susbtituted by the aliphatic or aromatic radicals mentioned for R and R furthermore by hydroxy, lower alkoxy, such as that mentioned above, hydroxy-lower alkyl, such as 2-hydroxy ethyl, 2 or 3-hydroxy-propyl or 2,3-dihydroxy-propyl, carboXy-lower alkyl or carbo-lower alkoxy-lower alkyl, such as carboxymethyl, 2-carboxyethyl, carbethoxymethyl or 3-carbomethoXy-propyl, or heterocyclic aryl, such as pyridyl, e.g. 2-, 3- or 4-pyridyl, thienyl, e.g. 2-thienyl or furyl e,g. 3-furyl.

An amino group R may also be unsubstituted or substituted as shown for R It preferably contains besides hydrogen or lower alkyl one of the aliphatic or aromatic radicals mentioned as substituent of the imino group R An aliphatically substituted hydroxy or mercapto group R is especially lower alkoxy or lower alkylmercapto, hpt may also be a hydroxy or mercapto group containing those aliphatic radicals shown for R and R The azacyclic arylidenemethyl group representing R, has, for example, the formula in which R is above all hydrogen, but may also stand for for one of the radicals listed for R and R and Q stands for an N-substituted monoor polycyclic, especially bicyclic, azacyclic arylidene radical, such as a l-substituted 2- or 4-pyridylidene or 2- or 4-quinolylidene, radical, a 2-substituted l-isoquinolylidene radical, a 3-substituted 2- thiazolylidene, 2-benzothiazolylidene, 2-oxazoylidiene or 2-benzoxazolylidene radical or a 1,3,3-trisubstituted 2-indolylidene radical in which the ring-nitrogen is part 'of an enamine grouping.

In the above azacyclic radicals represents Q, the substituent of the ring-nitrogen atom is above all a lower alkyl radical or one of the other radicals listed under R and R Apart from the group substituting the ring-nitrogen atom, the azacyclic ring is unsubstituted or may have one or more than one additional substituent, such as lower alkyl, etherified hydroxy, e.g. lower alkoxy, esterified hydroxy, e.g., halogeno, trifluoromethyl, etherified mercapto, e.g. lower alkylmercapto, nitro or disubstituted amino, e.g. di-lower alkyl-amino, of the meaning given above.

The ion An is above all the anion of an acid, primarily the anion of the inorganic acid, especially of a hydrohalic acid, e.g. hydrochloric, hydrobrornic or hydriodic acid, or of sulfuric, thiocyanic or perchloric acid, as well as the anion of an organic acid, such as a carboxylic or sulfonic acid, e.g. acetic, oxalic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric, benzoic or salicyclic acid or more especially of methane, ethane or 2-hydroxyethane sulfonic, 1,2-ethane disulfonic, benzene sulfonic, p-toluene sulfonic or 2-naphthalene sulfonic acid or of a monobasic organic sulfuric acid, such as a lower alkyl sulfuric acid, e.g. methyl or ethyl sulfuric acid, as well as the anion of an acidic organic nitro compound, e.g. picric, picrolonic or fiavianic acid or of a metal complex acid, e.g. phosphotungstic, phosphomolybdic, chloroplatinic or Reinecke acid. In the event that the compounds of this invention are used for pharmaceutical purposes, the anion An is that of a pharmaceutically accepted acid.

The compounds of this invention have valuable pharmacological properties. For example, they exhibit antimicrobial etfects, such as against gram-positive bacteria, e.g. Diplococcus pneumoniae, Staphylococcus aureus and the like, against gram-negative bacteria, e.g. Escherichia coli, Pseudomonas aeruginosa, Salmonella cholerasius and the like, against acid-fast bacteria, e.g. Microbacterium tuberculosis and the like, against fungi, e.g. Candida albicans, Cryptococus neoformans, Histoplasma capsulatum, Trichophyton mentagroplzytcs and the like, as well as against protozoa, e.g. T riclzomonas vagilmlis and the like. They are, therefore, useful as antimicrobial agents, either topically or systemically, against bacterial, fungal, or protozoal infections. They also show activities against helmints, such as Nippostrongylus muris and the like, which can be demonstrated, for example, in mice at oral doses between about 50 and 250 mg./kg./day, preferably at about mg./ kg./ day. They are, therefore, also useful as anthelmintic agents. Furthermore they exhibit anti-inflammatory effects, especially those compounds of Formulae I and II in which R and R stands for an imino or amino group respectively. This can be demonstrated, for example, in the granuloma pouch test or the carrageenin rat paw test, at oral does between about 5 and 50 mg./kg./day, preferably between about 10 and 25 mg./kg./day. They are, therefore, useful as anti-inflammatory agents, preferably for oral application, in place of cotrticosteroids, such as cortisone or hydrocortisone, in the treatment of tissue inflammations, such as arthritic inflammations and similar conditions.

The compounds of Formula II in which R, stands for an N-substituted azacyclic arylidene-methyl group represent cyanine dyes containing at least two auxochromic nitrogen atoms, one being of tertiary, the other of quaternary characteristics. One of these nitrogen atoms is the ring member of one heterocyclic ring system, the second of another heterocyclic ring system, and both are linked with each other through a chain of conjugated double bonds. These dyes are also excellent sensitizers of photographic emulsions without causing excessive fog or residual dye stain.

Especially useful are the compounds of the formulae in which A stands for alkylene having from three to five carbon atoms, each of the groups R and R for alkyl having up to 12 carbon atoms, monocyclic carbocyclic aryl-lower alkyl or monocyclic carbocyclic aryl, R for hydrogen, lower alkyl, amino-lower alkyl, monoor di-lower alkylamino-lower alkyl, alkyleneimino-lower alkyl in which alkylene has from four to six carbon atoms, azaoxaor thiaalkyleneimino-lower alkyl in which the heteroatom is separated from the ring-nitrogen by at least two carbon atoms and the ring has from four to six carbon atoms, carboxy-lower alkyl or carbo-lower alkoxy-lower alkyl, R for lower alkylmercapto, di-lower alkylamino or an at most bicyclic N lower alkyl-azacyclic, -thiazacyclic or oxazacyclic arylidenemethyl group in which the ring-nitrogen is part of an enamine grouping and An for a halogenid ion.

Particularly valuable are those compounds of the Formulae III and IV, in which A stands for 1,4-butylene, R for alkyl with up to 12 carbon atoms, phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (halogeno)-phenyl, (lower alkylmercapto)-phenyl or (nitro)-pheny1, R for phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (halogeno)-phenyl, (lower alkylmercapto)-phenyl or (nitro)-phenyl, R for lower alkyl, R for lower alkylmercapto, di-lower alkylamino, I-lower alkyl-2-or -4-pyridylidenemethyl, -2- or -4-quinolylidenemethyl, 2-lower alkyl-1-isoquinolylidenemethyl, 3-lower alkyl-Z-thiazolylidenemethyl, -2-benzothiazolylidenemethyl, -2-oxazolylidenemethyl, -2-benzoxazolylidenemethyl or 1,3,3-trilower alkyl-2-indolylidenernethyl or one of these radicals having lower alkyl, lower alkoxy, halogeno, lower alkylmtrcapto, nitro or di-lower alkyl-amino as substituents, and An for a halogenid ion.

(a) reacting a compound of the formula I Ra with the amine R -NH or (b) treating a compound of the formula will i i (VI) in which X stands for an x0 or thiono group, with ammonia, a primary amine or a reactive ester of an aliphatic alcohol and, if desired, treating a reaction product obtained from the reactive ester, with ammonia, an amine containing at least one hydrogen atom or a quaternary N-substituted azacyclic arylmethyl compound of which the methyl group contains at least two hydrogen atoms and the ring-nitrogen is capable of forming an enamine grouping and/or treating a product obtained, containing a free or mono-substituted imino or amino group respectively, with a reactive ester of an aliphatic or aromatic alcohol .and/ or converting in a quaternary compound obtained, the anion into the hydroxyl ion or another anion.

A reactive ester of the aliphatic alcohol used in reaction (b) is, for example, an ester of an inorganic acid, particularly a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydriodic acid, as well as of sulfuric acid, or of a suitable organic acid, especially a strong organic sulfonic acid, e.g. methane sulfonic, Z-hydroxyethane sulfonic or p-toluene sulfonic acid.

The quaternary arylmethyl compound more particularly is that of the formula [Q -CH --R An in which Q stands far a quaternary N-substituted azacyclic aryl group capable of furnishing the group Q. Q is more especially a quarternary 2- or 4-pyridyl, 2- or 4-quinolyl, l-isoquinolyl, Z-thiazolyl, 2-benzothiazolyl, 2-oxazolyl, 2-benzoxazolyl or 3,3-disubstituted Z-indolenyl group in which the group attached to the quaternary nitrogen atom is above all lower alkyl, whereas R has the previouslygiven meaning, but represents primarily hydrogen, and A11 is above all a halogenid iron.

The above reactions are carried out in the usual manner by combining the reactants in the absence or advantageously in the presence of a diluent, prefer-ably such that is inert to the reactants and is a solvent thereof, in the presence or absence of a catalyst, condensing or neutralizing agent, while cooling, at room temperature or advantageously at elevated temperatures, under atmospheric or superatmospheric pressure and/or in the atmosphere of an inert gas, e.g. nitrogen.

A neutralizing agent is preferably used in the reaction with the reactive esters and quaternary arylmethyl compounds. Such agent is, for example, an alkali or alkaline earth metal lower alkoxide or carbonate, e.g. sodium, potassium, magnesium or barium methoxide, ethoxide, npropoxide, isopropoxide or n-butoxide, sodium, potassium or calcium carbonate, or, more especially an organic base, such as pyridine or collidine, but particularly an aliphatic tertiary amine, such as a tri-lower alkylamine, e.g. trirnethylamine, N,N-dimethyl-N-ethyl-amine or triethylamine, as well as an N,N,N',N-tetra-lower alkyl-alkylenediamine, e.g. tetramethyl-1,6-hexylenediamine, an N-lower alkyl-alkyleneimine, e.g. N-methyl-pyrrolidine, N-methylpiperidine or N-ethyl-piperidine, an N-lower alkyl-morpholine, e.g. N-methyl-morpholine or a mixture thereof, such as a mixture of pyridine and triethylamine.

In a resulting quaternary compound the anion may be converted into another anion according to known methods. Thus, the anion of an acid may be replaced by the hydroxyl ion, for example, by reacting a resulting quaternary halide with silver oxide or a quaternary sulfate with barium hydroxide, by treating a quaternary salt with an anion exchange preparation, or by electrodialysis. From a resulting quaternary hydroxide, there may be obtained quaternary salts by reacting the quaternary base with an acid, for example, one of those previously mentioned. A resulting quaternary salt may also be converted directly into another quaternary salt without the formation of an intermediate quaternary hydroxide. For example, a quaternary iodide may be reacted with freshly prepared silver chloride or with hydrochloric acid in anhydrous methanol to yield the quaternary chloride; a quaternary salt may also be converted into another quaternary salt by treatment with an anion exchange preparation.

The starting materials used in the above procedure are new and are intended to be included within the scope of this invention. They are especially those corresponding to the compounds of Formulae III and IV.

The starting materials used in the above procedure are example, by reacting an enamine compound of the formula VII in which R stands for hydrogen, with a compound of the formula R CON=C=X, in which X stands for 0x0 or thiono and, if desired, converting in a resulting compound having an oxo group in the 4-position of the pyrimidine portion, such. group into the thiono group.

The compounds of Formula VII are prepared by treating the corresponding saturated cyclic ketone with the amine R NHR if necessary, while removing water, for example, by azeotropic distillation. The N-acylated isocyanate and N-acylated isothiocyanate reagents may be obtained, for example, by reacting silver nitrate with an alkali metal, e.g. sodium or potassium, isocyanate or isothiocyanate in the presence of a suitable diluent, e.g. diethyl ether and adding the slurry of the resulting silver isocyanate or silver isothiocyanate to a diethyl ether solution of the acyl halide R COHal. The resulting precipitate is filtered off, the filtrate is evaporated and, if necessary, the desired N-acyl-isocyanate or N-acyl-isothiocyanate compound is purified, for example, by distillation.

Said starting materials are also obtained, for example, by reacting an enamine compound of the Formula VII, in which each of R and R stands for lower alkyl or, more especially, together for alkylene with four to seven carbon atoms, particularly 1,4-butylene or 1,5-pentylene as well as 3-oxa-l,5-pentylene, with a compound of the Formula R CON=C=X and reacting the resulting compound of the formula 2 (VIII) with the amine R -NH and, if desired, converting prior or after said reaction an oxo group X into the thiono group.

The starting materials of Formula VI, particularly those, in which R and R represent aryl radicals, are also prepared by reacting an enamine compound of the Formula VI in which R and R have the last-given meaning, with an imidoylisocyanate or isothiocyanate compound of the formula and, if desired, converting in a resulting compound an oxo group into the thiono group. The imidoyl-isocyanate and imidoyl-isothiocyanate reagents are prepared from the corresponding halides, e.g. chlorides, by treatment with a metal, e.g. potassium or lead, cyanate or thiocyanate.

The conversion of an oxo group in the 4-position of the pyrimidine portion may be carried out, for example, by treatment with phosphorus pentasulfide in the presence of a high-boiling solvent, e.g. xylene.

The starting materials used in reaction (a) are prepared, for example, by reacting the intermediate compounds of the Formula VIII with a reactive ester of an aliphatic alcohol and, if desired, converting in the resulting compound the etherified hydroxy or mercapto group into an amino group or an N-substituted azacyclic arylidenemethyl group analogous to reaction (b).

The present invention also comprises any modification of the process, wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions or are used in the form of their salts.

In the process of this invention, those starting materials are preferably used which lead to final products mentioned hereinbefore as being the preferred embodiments of the invention.

The compounds of this invention are useful in the form of compositions for enteral, parenteral or topical administration, which contain a pharmacologically effective amount of the compounds of this invention in admixture with a pharmaceutically acceptable, organic or inorganic, solid or liquid, carrier, which usuall represents the major portion of the pharmaceutical composition. For making up the latter, there are employed carrier materials suitable for the preparation of pharmaceutical compositions, such as water, gelatin, sugars, e.g. lactose, glucose or sucrose, starches, e.g. corn starch, wheat starch or rice starch, stearic acid or salts thereof, e.g. calcium stearate or magnesium stearate, talc, vegetable oils, ethyl alcohol, benzyl alcohol, cetyl alcohol, petrolatum, gums, accacia, propylene glycol, polyalkylene glycols or any other known carrier for pharmaceutical compositions. The pharmaceutical preparations may be in solid form, e.g. capsules, tablets or dragees, in liquid form, e.g. solutions or suspensions, or in the form of emulsions, e.g. salves or creams. If desired, they may contain auxiliar substances, such as preserving, stabilizing wetting, emulsifying or coloring agents, salts for varying the osmotic pressure or buffers. The above preparations are prepared according to the standard methods used for the manufacture of pharmaceutically acceptable compositions, which, if desired, may contain, in combination, other physiologically useful substances.

In order to be used as syanine dyes in the sensitization of photographic silver halide emulsions, the arylidenemethyl compounds of this invention are dispersed in the emulsions, such as gelatino-silver halide emulsions, e.g. gelatino-silver bromide, gelatino-silver bromo-iodide, gelatino-silver chloride or gelatino-silver chloro-iodide. The methods of incorporating these dyes in emulsions are conventional and are described in the art.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade and all parts wherever given are parts by weight.

8 EXAMPLE 1 A mixture of 6.2 g. of l,2-diphenyl-5,6,7,8-tetrahydro- 1H-quinazolin-4-thione and 2.8 g. of methyl iodide in 200 ml. of acetone is refluxed for two hours. A yellow precipitate is formed which is filtered off and recrystallized from acetone to yield the 1,2-diphenyl-4-methylmercapto-5,6,7,8-tetrahydro-quinazolinium iodide of the formula which melts at 261-263"; yield: 5.3 g.

The starting material used in the above procedure is prepared as follows: A mixture of 98.0 g. of cyclohexanone and 131.0 g. of morpholine in 300 ml. of benzene is refluxed overnight while separating the generated water in a water separator. The benzene is removed and the l-(4-morpholino)-cyclohexene is distilled and collected at 182-185/125 mm.

A solution of 55.0 g. of 1-(4-morpholino)-cyclohexene in 45 ml. of chloroform is added to 107 g. of N-benzoylisothiocyanate in 150 ml. of chloroform over a period of one hour while cooling and stirring in an atmosphere of nitrogen. The ice-bath is removed, and the reaction mixture is refluxed for thirty minutes and is then allowed to stand overnight. The precipitate is filtered off, and washed with diethyl ether and methanol; the 2-phenyl-5,6,7,8- tetrahydro-l,3-benzoxazin-4-thione melts at 197-199 after recrystallization from N,N-dimethylformamide.

A mixture of 5.0 g. of 2-phenyl-5,6,7,S-tetrahydro-l, 3-benzoxazin-4-thione and 15.0 g. of aniline is refluxed for one hour. After cooling, 50 ml. of ethanol is added, and refluxing is continued for two additional hours. The crystalline material is filtered off; the l,2-diphenyl-5,6,7, S-tetrahydro-lH-quinazolin-4-thione of the formula melts at 262-263 after recrystallization from ethanol; yield: 4.2 g.

The starting material used in the above procedure is also prepared as follows: A mixture of 50.0 g. of cyclohexanone and 70.0 g. of aniline in 200 ml. of benzene is refluxed for 2% days using a water-separator to remove the generated water. The solvent is removed under reduced pressure, and the residue is distilled to yield the l-anilino-cyclohexene, which is collected at 1061l1/ 1 mm.

To a solution of 5.5 g. of N-benzoyl-isothiocyanate in 20 ml. of diethyl ether is added over a period of thirty minutes 8.0 g. of l-anilino-cyclohexene in 20 ml. of diethyl ether while cooling and maintaining an atmosphere of nitrogen. The orange precipitate is filtered off and washed with diethyl ether and methanol to yield the N- phenyl -thionoanthranilic acid N -benzoylamide, which melts at -87.

A solution of 0.3 g. of N-phenyl-thionoanthranilic acid N-benzoyl-amide in ml. of tetrahydrofuran is refluxed for one hour; an additional 90 ml. of tetrahydrofuran is added, and refluxing is continued for two hours. The precipitate is collected to yield the 1,2-diphenyl-5,6,7,8- tetrahydro-1H-quinazolin-4-thione, M.P. 265267.

The latter is also obtained directly by adding over a period of one hour, 6.0 g. of l-anilino-cyclohexene in 25 ml. of tetrahydrofuran to a solution of 5.5 g. of N-benzoylisothiocyanate in 25 ml. of tetrahydrofuran while cooling in an ice bath under at atmosphere of nitrogen. The precipitate is recrystallized from ethanol to yield the desired 1,2 diphenyl tetrahydro 1H 5,6,7,8 quinazolin 4- thione, M.P. 263-265.

The starting material may also be obtained according to the following procedure: A mixture of 23.9 g. of benzoic acid N-phenyl-amide and 22.0 g. of thionyl chloride is refluxed on the steam bath for six hours; the excess of thionyl chloride is evaporated under reduced pressure, the residue crystallizes upon cooling and is recrystallized from pentane to yield the N-phenyl-benzimidoyl chloride, which melts at 40; yield: 19.5 g., and is identical with the compound described by von Braun et al., Ber., vol. 67, p. 1218 (1934).

A mixture of 2.15 g. of N-phenyl-benzimidoyl chloride and 3.23 g. of lead thiocyanate in 30 ml. of dry benzene is refluxed for two hours. The mixture is filtered and evaporated to dryness under reduced pressure. The residue is triturated with dry pentane; the solid material is filtered off and the filtrate is evaporated to dryness under reduced pressure at room temperature. The residue is dissolved in ml. of dry p-dioxane, and the solution containing the -N-phenyl-benzimidayl isothiocyanate is cooled in an ice-bath. To this solution is added dropwise 1.57 g. of 1 (4 morpholino) cyclohexene while cooling. Upon standing overnight at room temperature, the 1,2-diphenyl- 5,6,7,8 tetrahydro 1H quinazolin 4 thione precipitates, M.P. 260-274.

EXAMPLE 2 A mixture of 3.8 g. of 1-n-decyl-2-phenyl-5,6,7,8-tetrahydro-1H-quinazolin-4-thione and 2.13 g. of methyl iodide in 50 ml. of acetone is shaken until a complete solution is obtained. The solvent is then removed under reduced pressure, and the desired 1-n-decyl-4-methylmercapto-2- phenyl-5,6,7,8tetrahydroquinazolinium iodide of the formula is obtained as a brown viscous oil, which is not further purified.

The starting material used in the above procedure is prepared as follows: A mixture of 4.0 g. of Z-phenyl- 5,6,7,8-tetrahydro-1,3-benzoxazin-4-thione and 10 ml. of n-decylamine in 50 ml. of ethanol is refluxed for twenty minutes. The resulting solid material is filtered off; the desired 1-n-decyl-2-phenyl-5,6,7,8-tetrahydro-IH-quinazolin- 4-thione of the formula lefin-(n H2 0 1120 o o-@ g H H2C\ /N C 0 H2 H S melts at 155-156 after recrystallization from ethanol.

10 EXAMPLE 3 A mixture of 4.1 g. of 1-(4-fiuoro-phenyl)-2-phenyl- 5,6,7,8 -tetrahydro-1H-quinazolin-4-thione and 1.7 g. of methyl iodide in 300 ml. of acetone is refluxed for four hours. After cooling, the precipitate is filtered off to yield the 1 (4-fluorophenyl)-4-methylmercaptoQ-phenyl-S,6, 7,8-tetrahydro-quinazoliniurn iodide of the formula I S-CHa which melts at 257258 after recrystallization from acetone.

The starting material used in the above procedure is prepared as follows: A mixture of 5.0 g. of 2-phenyl- 5,6,7,8-tetrahydro-1,3-benzoxazin-4-thione and 9.0 g. of 4- fluoro-aniline in 50 ml. of ethanol is refluxed for four hours. The yellow precipitate is filtered off and recrystallized from ethanol to yield the 1-(4-fluoro-phenyl)-2- phenyl-5,6,7,8-tetrahydro-1H-quinozalin-4-thione of the formula which melts at 307-310.

EXAMPLE 4 The 1-(4-fluoro-phenyl)-4-methylmercapto-2-(4-rnethylphenyl)-5,6,7,8-tetrahydro-quinazolinium iodide is obtained by reacting a mixture of 6.7 g. of 1-(4-fluorophenyl)-2-(4-methylphenyl)-5,6,7,8-tetrahydro lH-quinazolin-4-thione and 2.8 g. of methyl iodide in 200 ml. of ethanol according to the procedure described in Example 1.

The starting material used in the above procedure is prepared as follows: To a cold solution of 7.5 g. of 4- fluoro-aniline in 25 ml. of pyridine is added dropwise 10.5 g. of crude 4-methyl-benzoyl chloride. The resulting mixture is poured into approximately 250 ml. of water; the precipitate is filtered off, dried and recrystallized from methanol using a charcoal preparation for decolorization. The desired 4-methyl-benzoyl N-(4-fluoro-phenyl)- amide melts at -188.

A mixture of 10.0 g. of 4-methyl-benzoyl N-(4-fiuoropheny1)-amide and 25 ml. of thionyl chloride is refluxed overnight and is then evaporated under reduced pressure. The residue is recrystallized from a mixture of diethyl ether and pentane to yield the N-(4-fluoro-phenyl)-4- methyl-benzimidoyl chloride, M.P. 88-91".

A mixture of 5.6 g. of N-(4-fluoro-phenyl)-4-methylbenzimidoyl chloride and 7.45 g. of lead thiocyana-te in 50 ml. of dry benzene is refluxed for two hours and is then filtered. The filtrate is concentrated to dryness under reduced pressure and the residue is triturated with dry pentane. The solid material is filtered off; the pentane solution is concentrated and cooled to yield the N-(4-fluorophenyl)-4-methyl-benzimidoyl isothiocyanate which melts at 77-79 after recrystallization from pentane.

To a solution of 1.67 g. of 1-(4-morpholino)-cyclohexene in ml. of dry p-dioxane is added dropwise a solution of 2.7 g. of the N-(4-fiuoro-phenyl)-4-methylbenzimidoyl isothiocyanate in ml. of dry p-dioxane. The solution is allowed to stand at room temperature overnight after having been seeded with a small amount of 1- (4-fluoro-phenyl -2- 4-methyl-phenyl -5,6,7,8-tetrahydro-1H-quinazolin-4-thione. The product melts at 291- 293 after recrystallization from acetone.

EXAMPLE 5 The 2-(4-chloro-phenyl)-l-(4-fluoro-phenyl)-4-methylmercapto-5,6,7,8-tetrahydro-quinazolinium iodide is prepared by reacting a mixture of 7.1 g. of 2-(4-chlorophenyl)-l-(4-fluoro phenyl) 5,6,7,8 tetrahydro 1H- quinazolin-4-thione and 3.0 g. of methyl iodide in 200 ml. ethanol as described in Example 1.

The starting material used in the above procedure is prepared as described in Example 4, i.e. by reacting 4-chlorobenzoyl chloride with 4-fluoro-aniline, treating the resulting 4-chloro-benzoyl N-(4-fluoro-phenyl)-amide (M.P. 179l8l after recrystallization from ethanol) with thionyl chloride, converting the N-(4-fluoro-phenyl) 4-chloro-benzimidoyl chloride (M.P. 78-80 after recrystallization from pentane) into the N-(4-fluoro-phenyl) 4-ch1oro-benzimidoyl isothiocyanate by treatment with lead thiocyanate, and reacting the N-(4-fluoro-phenyl) 4-chloro -benzimidoyl isothiocyanate (M.P. 85-87" after recrystallization from pentane) with l-(4-morpholino) cyclohexene; the 2-(4 chloro phenyl) 1-(4 fluorophenyl)-5,6,7,8-tetrahydro-1H-quinazolin-4-thione of the formula melts above 300 after recrystallization from acetone.

EXAMPLE 6 A mixture of 7.0 g. of 1-(4-fiuoro-phenyl)-2-(4-methoxy-phenyl)-5,6,7,8-tetrahydro-lH-quinazolin 4 thione and 3.0 g. of methyl iodide in 200 ml. of ethanol, when reacted as described in Example 1 yields the 1-(4-fiuorophenyl)-2-(4 methoxy-phenyl) 4 methylmercapto- 5,6,7,8,tetrahydro-quinazolinium iodide.

The starting material used in the above procedure is prepared as described in Example 4, i.e. by reacting 4- methoxy-benzoyl chloride with 4-fluoro-aniline to form the 4-methoxy-benzoyl N-(4-fiuoro-phenyl)-amide, which is treated with thionyl chloride; the resulting N-(4-fiuorophenyl)-4-rnethoxy-benzimidoyl chloride is reacted with lead thiocyanate, and the N-(4-fluoro-phenyl) 4-methoxybenzimidoyl isothiocyanate is converted into the l-(4-fiu- 12 orophenyl)-2-(4 methoxyphenyl) 5,6,7,8 tetrahydrolH-quinazolin-4-thione of the formula by reacting it with 1-(4-morpholino)-cyclohexene.

EXAMPLE 7 Other compounds of this invention, which are prepared according to the above-described and illustrated procedure by selecting the appropriate starting materials, are, for example, 1,2-diphenyl-4-methylmercapto cyclopenta [e]pyrirnidinium iodide, prepared by reacting cyclopentanone with morpholine and removing the generated water, reacting the 1-(4-morpholino)-cyclopentene with N benzoyl-isothiocyanate, and the resulting Z-phenyl-cyclopenta [e] 1,3-benzoxazir1-4-thione with aniline, and quaternizing the 1,2-diphenyl-1,4-dihydro cyclopenta[e]pyrimidin 4- thione with methyl iodide;

1-(4-rnethoxy-phenyl)-4-methylmereapto 2 phenylcyclopenta[e]pyrimidinium iodide, prepared by reacting 2-phenyl-cyclopenta[e]1,3-benzoxazin 4 thione with p-anisidine, and quaternizing the 1-(4-methoxy-pheny1)- Z-phenyl-1,4-dihydro-cyclopenta[e]pyrimidin 4 thione with methyl iodide;

2-benzyl-1-(4-chloro-phenyl)-4-ethylmercapto 5,6,7,8- tetrahydro-quinazolinium iodide, prepared by reacting 1- (4-morpholino)-cyclohexene with N-phenacetyl-isothiocyanate, treating the resulting 2-benzyl-5,6,7,S-tetrahydro- 1,3-benz0axazin-4-thione with 4-chloro-aniline, and quaternizing the 2-benzyl-1-(4-ch1oro-phenyl)-5,6,7,8 tetrahydro-lH-quinazolin-4-thione with ethyl iodide;

4-benzyl mercapto-Z-ethyl 1 (4 methyl phenyl)- 5,6,7,S-tetrahydroquinazolinium bromide, prepared by reacting 1-(4-morpholino)-cyclohexene with N-propionylisothiocyanate, treating the resulting 2-ethyl-5,6,7,8-tetrahydro-1,3-benzoxazin-4-thione with p-toluidine, and quaternizing the 2-ethyl-1-(4-methyl-phenyl) 5,6,7,8 tetrahydro-1H-quinazolin-4-thione with benzyl bromide;

2- (4-bromo-phenyl) 1 methyl 4 methylmercapto- 5,6,7,8-tetrahydroquinazolinium iodide, prepared by reacting 1-(4-morpholino)-cyclohexene with N-(4-bromo-benzoyl)-isothiocyanate, treating the resulting 2- (4-bromophenyl)-5,6,7,8-tetrahydro-1,3-benzoxazin-4-thione with methylamine, and quaternizing the 2-(4-bromo-phenyl)-1- methyl-5,6,7,8-tetrahydro-lH-quinazolin 4 thione with methyl iodide;

4-methylmarcapto 2 phenyl 1 (4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-quinazolinium iodide, prepared by reacting 2-phenyl-5,6,7,8-tetrahydro-1,3-benz0xazine-4- thione with p-trifiuoromethylaniline and quaternizing the 2 phenyl-l-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro- 1H-quinazolin-4-thione with methyl iodide;

4-methylmarcapto 2 (3-nitro-phenyl) 1 phenyl- 5,6,7,8-tetrahydroquinazolinium iodide, prepared by reacting 1-(4-morpholino)-cyclohexene with N-(3-nitro-benzoyl)-isothiocyanate, treating the resulting 2-(3-nitrophenyl)-5,6,7,8-tetrahydro 1,3 benzoxazin-4-thione with aniline, and quaternizing the 2-(3-nitro-phenyl)-1-phenyl- 5,6,7,8-tetrahydro-1,3-benzoxazin-4-thione with methyl iodide;

4-methylmarcapto 1 (4-methylmarcapto-phenyl -2- phenyl-5,6,7,8-tetrahydro-quinazolinium iodide, prepared by reacting 2-pheny1-5,6,7,8-tetrahydro-1,3-benzoxazine-4- thione with 4-methylmarcapt0aniline and quaternizing the 13 1-(4-methylmarcapto-phenyl) 2 phenyl-5,6,7,8-tetrahydro-lH-quinazolin-4-thione with methyl iodide;

1-benzyl-6-methyl-4-methylmarcapto-2-phenyl 5,6,7,8- tetrahydroquinazolinium iodide, prepared by reacting 4- methyl-cyclohexanone with morpholine and removing the generated water, treating the 4-methyl-1-(4-morpholino)- cyclohexene with N-benzoyl-isothiocyanate, reacting the resulting 6-methyl-2-phenyl-5,6,7,8-tetrahydro 1,3 benzoxazine-4-thione with benzylamine, and quaternizing the l-benzyl 6 methyl 2 phenyl-5,6,7,8-tetrahydro-1H- quinazolin-4-thione with methyl iodide;

1,2-dipheny1-4-methylmarcapto cyclohepta [e]pyrimidinium iodide, prepared by reacting cycloheptanone with morpholine and removing the generated water in a water separator, treating the 1-(4-morpholino)-cycloheptene with N-benzoyl-isothiocyanate, reacting the resulting 2-phenyl-cyclohepta[e]1,3-benzoxazin-4-thione with aniline, and quaternizing the 1,2-diphenyl-1,4-dihydro-cyclohepta[e]pyrimidine with methyl iodide; and the like.

EXAMPLE 8 A mixture of 1.0 g. of 4-(3-methyl-2=benzothiazolylidenemethyl) 2 phenyl-5,6,7,8-tetrahydro-1,3-benzoxazinium iodide and 10 ml. of aniline is refluxed for one hour. After chilling, a precipitate is formed, which is filtered off and Washed with diethyl ether to yield the 1,2- diphenyl-4-(3-methyl 2 benzothiazolylidene-methyl)- 5,6,7,8-tetrahydro-quinazolinium iodide of the formula which melts at 312-3 14 after recrystallization from ethanol.

Other compounds, which are prepared by reacting 4-(3- methyl-Z-benzothiazolylidene-methyl) 2 phenyl-5,6,7,8- tetrahydro 1,3-benzoxazinium iodide with an amine, such as 4-fluoro-aniline, N,N-diethyl 1,2 ethylenediamine, n-propylamine, methylamine, N,N-dimethyl-1,2-ethylenediamine, 3-amino-pyridine, N,N-diethyl-1,4-phenylencdiamine and the like, are, for example, l-(4-fluoro-phenyl)- 4-(3-methyl-Z-benzothiazolylidene-methyl) 2 phenyl- 5,6,7,8-tetrahydro-quinazolinium iodide, M.P. 27l272 after recrystallization from ethanol; and 1-(2-N,N-diethylaminoethyl)-4-(3 methyl-2-benzothiazolylidene-methyl-2-phenyl-5,6,7,8-tetrahydro quinazolinium iodide, M.P. 194l96 after recrystallization from ethanol; as well as 4-(3-methyl-2-benzothiazolylidene-methyl) 2 phenyl-1- n-propyl 5,6,7,8 tetrahydro-quinazolinium iodide, M.P. 245-246" after recrystallization from ethanol; 1-methyl-4- (3-methyl 2 benzothiazolylidene-methyl) 2 phenyl- 5,6,7,8-tetrahydro-quinazolinium iodide, 1 (2 dimethylamino-ethyl)-4-(3-methyl 2 benzothiazolylidene-methyl)-2-phenyl-5,6,7,8-tetrahydro-quinazolinium iodide, M.P. 228230 after recrystallization from methanol; 1-(3- pyridyl)-4-(3-methy l -2 benzothiazolylidene-methyl)-2- phenyl 5,6,7,8 tetrahydro-quinazolinium iodide, M.P. 266-267 (decomp) after recrystallization from methanol; l (4-diethylamino-phenyl)-4-(3-methyl-2-benzothiazolylidene-methyl) 2 phenyl-5,6,7,8-tetrahydro-quinazolinium iodide, and the like.

The starting material used in the above procedure is prepared as follows: A mixture of 5.0 g. of 2-phenyl- 5,6,7,8-tetrahydro-1,3 benzoxazin-4-thione and 4.5 g. of

which melts at 3l3-314 after recrystallization from methanol.

EXAMPLE 9 A mixture of 3.2 g. of 4-(1-ethyl-2-quinolylidene-methyl)-2-phenyl-5,6,7,8-tetrahydro-1,3benzoxaziniurn iodide and 20 ml. of 4-fluoro-aniline, when reacted as described in Example 8, yields the 4-(1-ethyl-2-quinolylidene-methly)-1-(4-fiuoro-phenyl) 2 phenyl 5,6,7,8 tetrahydroquinazolinium iodide of the formula which melts at 252253 after recrystallization from ethanol.

The starting material used in the above procedure is prepare as follows: A mixture of 10.0 g. of 4-methylmercapto 2 phenyl 5,6,7,8 tetrahydro 1,3 benzoxazinium diodide and 7.8 g. of 2-quinaldine ethiodide in ml. of ethanol containing 4 ml. of N,N,N-triethylamine is refluxed for 2 /2 hours. After cooling, the precipitate is filtered off to yield the 4-(l-ethyl-2-quinolylidenemethyl)-2-phenyl-5,6,7,S-tethrahydro-1,3 benzoxazinium iodide of the formula which melts at 256-258 (with decomposition).

EXAMPLE 10 A mixture of 2.5 g. of 1,2-diphenyl-4-methylmercapto- 5,6,7,8-tetrahydro-quinazolinium iodide and 1.6 g. of 2,-

methylbenzothiazole methiodide in 50 ml. of ethanol and 2 ml. of N,N,N-triethylamine is refluxed for twentyfour hours. After cooling, the precipitate is filtered off and recrystallized from ethanol to yield the 1,2-diphenyl-4-(3- methyl-2-benzothiazolylidenemethyl)-5,6,7,8tetrahydroquinazolinium iodide, M.P. 3l2-3l4, which is identical with the compound obtained according to the procedure described in Example 8.

EXAMPLE 11 EXAMPLE 12 A mixture of 0.5 g. of 1-(4-fiuoro-phenyl)-4-methylmercapto-2-phenyl-5,6,7,8 tetrahydro quinazolinum iodide and 0.3 g. of 2-quinaldine methiodide in 10 ml. of ethanol and 0.5 ml. of N,N,N-triethylamine, when reacted as described in Example 11, yields the l-(4 fluorophenyl) 4 (1 methyl 2 quinolylidene methyl) 2- phenyl-5,6,7,8-tetrahydro-quanazolinium iodide of the formula which melts at 220-223".

EXAMPLE 13 A mixture of 3.0 g. of 1-n-decyl-4-methylmercapto-Z- phenyl-5,6,7,8-tetrahydro-quinazolinium iodide and 2.25 g. of 2-methyl-benzothiazole methiodide in 50 ml. of ethanol containing a few drops of N,N,N-triethylamine is refluxed overnight. The solvent is partially removed under reduced pressure, and upon cooling the desired l-ndecyl 4 (3 methyl 2 benzothiazolylidene methyl)- 2-phenyl-5,6,7,S-tetrahydro-quinazolinium iodide of the formula C ioHtr-(n H:

/N 1110 o O-G e i I I 16 precipitates and is filtered off; it melts at 214-215" after recrystallization from ethanol.

EXAMPLE 14 Other compounds of this invention, which are prepared according to the above described and illustrated procedure, are the following:

1,2-diphenyl 4 (l-methyl pyridylidene-methyl)-cyclopenta[e]pyrimidinium iodide, prepared by reacting 1,2 diphenyl 4 methylmercapto-cyclopenta[e]pyrimidinium iodide with 2-picoline methiodide in the presence of N,N,N-triethylamine;

1,2-diphenyl 4 (3-methyl 2 benzothiazolylidinemethyl)-cyclopenta[e]pyrimidinium iodide, prepared by reacting the 2 phenyl-cyclopenta[e]l,3 benzoxazin-4- thione with methiodide, treating the 4-methylmercapto- 2-phenyl-cyclopenta[e]1,3-benzoxazinium diodide with 2- methyl-benzothiazole methiodide in the presence of N,N,N-triethylamine, and converting the resulting 4-(3- methyl 2 benzothiazolylidene-methyl)-2-phenyl-cycl0- penta[e]1,3-benzoxazinium iodide into the desired compound by treatment with aniline;

1,2-diphenyl 4 (1-ethyl-2-quinolylidene-methyl)-cyclopenta[e]pyrimidinum iodide, prepared by reacting 1,2-diphenyl 4 methylmercapto-cyclopenta[e]pyrimmidinium iodide with 2-quinaldine ethiodide in the presence of N,N,N-triethylamine;

1-(4-methoxy-phenyl) 4 (1-methyl-4pyridylideneidinium iodide with Z-quinaldine ethiodide in the prespared by reacting 1-(4-methoxy-phenyl)4-methylmercapto-Lphenyl-cyclopenta[e]pyrimidinium iodide with 4- picoline methiodide in the presence of N,N,N-triethylamine;

2-benzyl-1-(4-ch'loro-phenyl)-4-(3-methyl 2 benzothiazolyl-methyl) 5,6,7,8 tetrahydro quinazolinium iodide, prepared by reacting 2-benzyl-l-(4-chloro-phenyl)- 4-ethy1mercapto-5,6,7,8-tetrahydro-quinazolinium iodide with Z-methyl-benzothiazole methiodide in the presence of N,N,N-triethylamine;

2-ethyl-4-(2-methyl 1 isoquinolylidene-methyl)-1- (4-methy1-phenyl)-5,'6,7,8-tetrahydro-quinolinium iodide, prepared by reacting 2-ethyl-5,6,7,8-tetrahydro-1,3-benzoxazin-4-thione with methyl iodide, treating the 2-ethyl- 4-methylmercapto-5,6,7,8-tetrahydro 1,3 benzoxazinium iodide with l-methyl-isoquinoline methiodide in the presence of N,N,N-triethylamine, and treating the resulting 2-ethyl-4-(2-methyl 1 isoquino-lylidene-methyl) 5,6,7,8-tetrahydro 1,3 benzoxazinium iodide with ptoluidine;

2-ethyl-4-(3-methyl 2 benzothiazolylidene-methyl)- 1-(4-methyl-phenyl) 5,6,7,8 tetrahydro-quinazoliniurn iodide, prepared by reacting 4-benzylmercapto-2-ethyl-1- (4-methyl-phenyl) 5,6,7,8 tetrahydro-quinazolinium bromide with a large excess of sodium iodide in water and treating the 4-benzylmercapto-2-ethyl-1-(4-methylphenyl)-5,6,7,S-tetrahydro-quinazolinium iodide with 2- methyl-benzothiazole methiodide in the presence of N,N,N-triethylamine;

2-(4-bromo-phenyl) 4 (6-N,N-diethylamino-l-methyl-2-quinolylidene-methyl) 1 methyl-5,6,7,8-tetrahydro-quinazolinium iodide, prepared by reacting 2-(4- bromo-phenyl)-1-methy1 4 methylmercapto-5,6,7,8- tetrahydro-quinazolinium iodide with 6-N,N-diethylamino-Z-quinaldine methiodide in the presence of N,N,N- triethylamine;

4-(3-methyl 2 thiazolylidene-methyl)2-phenyl1-(4- trifluoromethyl-phenyl) 5,6,7,8 tetrahydro-quinazolinium iodide, prepared by reacting 4-methylmercapto-2- phenyl-l-(4-trifiuoromethyl-phenyl) 5,6,7,8 tetrahydro-quinazolinium iodide with Z-methyl-thiazole methiodide in the presence of N,N,N-triethylamine;

4-(1-methyl 4 quinolylidene-methyl) 2 (3-nitropihenyD-l-phenyl 5,6,7,8 tetrahydros-quinazolinium iodide, prepared by reacting 4-methylmercapto-2-(3-nitrophenyl) 1 phenyl 5,6,7,8 tetrahydro-quinazolinium iodide with 4-quinaldine rnethiodide in the presence of N,N,N-triethylamine;

1,2-diphenyl-4-(l-methyl 2 pyridy-lidene-methyl)- 5,6,7,8-tetrahydro-quinazolinium iodide, prepared by reacting 1,2-diphenyl 4 methylmercapto-5,'6,7,8-tetrahydro-quinazolinium iodide with 2-picoline rnethiodide in the presence of N,N,N-triethylamine;

1,2-diphenyl 4 (3-methyl-thiazolylidene-methyl)-5,6- 7,8-tetrahydro-quinazolinium iodide, prepared by reacting 4-methylmercapto 2 phenyl 5,6,7,8 tetrahydro-1,3- benzoxazinium iodide with 2-methyl-thiazole rnethiodide in the presence of N,N,N-triethylamine and reacting the 4-(3-methyl 2 thiazolylidene-methyl)-2-phenyl-5,6,- 7,8-tetrahydro-1,3-benzoxazinium iodide with aniline;

1,2-diphenyl 4 (3-ethyl 2 oxazolylidene-methyl)- 5,6,7,8-tetrahydro-quinazolinium iodide, prepared by reacting 1,2-diphenyl-4-methylmercapto-S,6,7,S-tetrahydroquinazolinium iodide with 2-methyl-oxazole ethiodide in the presence of N,N,N-triethylamine;

1,2-diphenyl 4 (S-methyl 2 benzoxazolylidenemethyl)-5,6,7,8-tetrahydro-quinazolinium iodide, prepared by reacting 1,2-diphenyl-4-methylmercapto-5,6,7,8-tetrahydro-quinazolinum iodide with 2-methyl-benzoxazole rnethiodide in the presence of N,N,N-triethylamine;

2-(4-chloro-phenyl) 1 (4-fluoro-phenyl)-4-(3-methyl-2-benzothiazolylidene-methyl) 5,6,7,8 tetrahydro quinazolinium iodide, prepared by reacting 2-(4chloro phenyl)-1-(4-fluoro-phenyl) 4 methylmercapto-S,6 ,7,8- tetrahydro-quinazolinium iodide with 2-methyl-benzothiazole rnethiodide in the presence of N,N,Ntriethylamine;

1-(4-fluoro-phenyl) 2 (4-methoxy-phenyl) 4 (1- methyl 2 quinolylidene-methyl)-5,6,7,8 tetrahydroquinazolinium ioidide, prepared by reacting 1-(4-fiuoropheny-l) 2 (4-methoxy-phenyl) 4 methylmercapto- 5,6,7,8-tetrahydro-quinazolinium iodide with Z-quinaldine rnethiodide in the presence of N,N,N-triethylamine;

4-(3-methyl 2 benzothiazolylidene-methyl) 1-(4- methylmercapto-phenyl)-2-phenyl 5,6,7,8 tetrahydroquinazolinium iodide, prepared by reacting 4-methylmercapto-l-(4-methylmercapto-phenyl) 2 phenyl-5,6,7,8- tetrahydro-quinazolinium iodide with Z-methyl-benzothiazole rnethiodide in the presence of N,N,N-triethylamine;

l-benzyl 6 methyl-4-(l-methyl 2 quinolylidenemethyl)-2Pphenyl '5,6,7,8 totrahydro-quinazolinium iodide, prepared by reacting 6-methyl-2-phenyl-5,6,7,8- tetrahydro-1,3-benzoxazin 4 thione with methyl iodide, treating the 6-methyl- 4 methylmercapto 2 phenyl- 5,6,7,8-tetrahydro 1,3 'benzoxaziniurn iodide with 2- quinaldine rnethiodide in the presence of N,N,N-triethylamine, and reacting the 6-methyl-4-(1-methyl-2-quinolylidene-methyl) 2 phenyl 5,6,7,8 tetrahydro-l,3- benzoxazinium iodide with benzylamine;

l-benzyl-4-(6-chloro-l-ethyl-4 quinolylidene methyl)- 2 phenyl 5,6,7, 8-tetrahydro quinazolinium iodide, prepared by reacting l-benzyl-6-methyl-4-methylmercapt0-2- phenyl-5,6,7,S-tetrahydroquinazolinium iodide with 6- chloro-4-quinaldine rnethiodide in the presense of N,N,N-triethylamine;

l,2-diphenyl-4-(1,3,3-trimethyl 2 indolylidene methyl)-5,6,7,8-tetrahydro-quinazolinium iodide, prepared by reacting 1,2-diphenyl-4-methylmercapto 5,6,7,8 tetrahydro-quinazolinium iodide with 2,3,3-trimethyl-indolenine rnethiodide in the presence of N,N,N-triethylamine;

1,2-diphenyl-4-(3-methyl-2-benzothiazolylidene methyl)-cyclohepta [e]pyrimidinium iodide, prepared by reacting 1,2-diphenyl-4-methylmercapto cyclohepta[e] pyrimidinium iodide with 2-methylbenzothiazole rnethiodide in the presence of N,N,N-triethylamine;

l-2-diphenyl-4-(6-methoxy-1-methyl 2 quinolylidenemethyl)-cyclohepta[e]pyrimidinium iodide, prepared by reacting 1,Z-diphenyl-4-methylmercapto-cyclohepta[e]py- 18 rimidinium iodide with 6-methoxy-2-quinaldine methiodide in the presence of N,N,N-triethylamine; and the like.

EXAMPLE 15 The mixture of 3.3 g. of 4-(3-n-butyl-2-benzoxazolylidcue-methyl)-2-phenyl-5,6,7,8-tetrahydro-1,3 beuzoxazinium iodide, 1.0 g. of n-decylamine and 250 ml. of methanol is refluxed for two hours. From the reaction mixture the methanol is distilled off and the remaining oil crystallizes on standing overnight. Upon recrystallization from 2-propanol there is obtained the pure yellow l-n-decyl-Z- phenyl-4-(3-n-butyl-2-benzoxazolylidene methyl)-5,6 ,7,- 8-tetrahydro-quinazolinium iodide of the formula melting at 75.

The starting material is prepared as follows:

10.0 g. of Z-methyI-benzoxazole and 17.0 g. of n-butyl iodide are mixed together and the whole is heated in a sealed tube to for 48 hours. The solid formed is recrystallized from ethanol to yield the 3-n-butyl-2-methylbenzoxazolinium iodide melting at 147150.

The mixture of 24.0 g. of 4-methylmercapto-2-phenyl 5,6,7,8-tetrahydro-1,3-benzoxazinium iodide, 13.0 g. of 3-n-butyl-2-methyl-benzoxazolinium iodide, 10 ml. of triethylamine and 50 ml. of methanol is refluxed for 4 hours. Upon cooling the solution is allowed to stand for one day and hereupon a small amount of diethyl ether is added. On cooling the 4-(3-n-butyl-2-benzoxazolylidene-methyl)- 2-phenyl-5, 6,7,S-tetrahydro-l,B-benzoxazinium iodide crystallizes out. It is filtered off, washed with ice cold methanol-ether and dried; M.P. 260.

In the analogous manner the following compounds are prepared by using the equivalent amounts of starting material:

(a) l-n-undecyl-2-phenyl-4-(3-ethyl-2-benzoxazolylidenemethyl)-5,6,7,8-tetrahydro-quinazolinium iodide, M.P. 181-183 after recrystallization from isopropanol;

(b) 1-n-octyl-2-phenyl-4-( 3 ethyl 2 benzoxazolylidenemethyl)-5,6,7,S-tetrahydro-quinazolinium iodide, M.P. 223-225 after recrystallization from isopropanol;

(c) l-n-decyl-2-phenyl-4-(3-n-propyl-2-benzoxazolylidenemethyl)-5,6,7,8-tetrahydro-quinazolinium iodide, M.P. 174l76 after recrystallization from isopropanol;

(d) 1-n-decyl-2-phenyl-4-(3-ethyl 2 benzoxazolylidenemethyl)-5,6,7,8-tetrahydro-quinazolinium iodide, M.P. l92 after recrystallization from isopropanol and (e) 1-n-decyl-2-phenyl-4-(3 methyl-2-benzoxazolylidenemethyl)-5,6,7,8-tetrahydro-quinazolinium iodide, M.P. 190-191 after recrystallization from isopropanol.

The different starting materials may be obtained as follows:

20.2 g. of 2methyl-benzoxazole and 64.0 g. of methyl iodide are dissolved in 100 ml. of acetone and the whole is stirred overnight at room temperature. The solid formed is filtered off and washed with acetone to yield the 2,3- dimethylbenzoxazolinium iodide melting at 199-200".

The mixture of 20.2 g. of Z-methyl-benzoxazole and 28.8 g. of ethyl iodide is heated in a sealed tube to 100 for 48 hours. Upon cooling the solid formed is recrystal- 19 lized from ethanol to yield the 3-ethyl-2-methyl-benzoxazolinium iodide melting at 195197.

The corresponding 3-n-pr0pyl-compound is prepared as the 3-ethyl compound from 30.0 g. of 2-methyl-benzoxazole and 45.9 g. of n-propyl iodide; M.P. 194196.

The 4-(3-methyl-2-benzoxazolylidene methyD-Z-phenyl-5,6,7,8-tetrahydro-l,3-benzoxazinium iodide used as starting material for the compound listed under (e) melts at 269.

The compound described in Example 12 may also be prepared according to the above described method from equivalent amounts of 4-(1-methyl-2-quinolylidene-methyl)-2-phenyl-5,6,7,8 tetrahydro-1,3-benzoxazinium iodide (melting at 274-275) and 4-fiuoro-aniline.

EXAMPLE 16 The mixture of 2 g. of 4-(3-ethyl-2-benzothiazolylidenemethyl)-2-phenyl 5,6,7,8 tetrahydro-1,3-benzoxazinium iodide and 5 ml. of 4-fluoro-aniline is refluxed for one hour. After chilling the reaction mixture and adding a small amount of diethyl ether, a precipitate is formed, which is filtered oii and washed with diethyl ether to yield the 1-(4-fluoro-phenyl)-2-phenyl-4-(3-ethyl-2-benzothiazolylidene-methyl)-5,6,7,8-tetrahydro quinazolinium iodide of the formula which melts at 285-287" after recrystallization from ethanol.

The starting material is prepared as shown in Example 8 and melts at 290291.

In the analogous manner the following compounds are prepared by using 2 g. of the iodide and 5 ml. of decylamine, 11 ml. of 4dimethylamino-aniline or 5 ml. of 2- diethylamino-ethylamine respectively:

(a) l n decyl 2 phenyl 4 (3 ethyl 2 benzothiazolylidene methyl) 5,6,7,8 tetrahydro quinazolinium iodide, M.P. 241-243 after recrystallization from ethanol,

(b) 1 (4 dimethylamino phenyl) 2 phenyl 4 (3- methyl 2 benzothiazolylidene methyl) 5,6,7,8- tetrahydro-quinazolinium iodide, M.P. 314-315" after recrystallization from methanol, and

(c) l (2 diethylamino ethyl) 2 phenyl 4 (3- methyl 2 benzothiazolylidene methyl) 5,6,7,8- tetrahydro-quinazolinium iodide, M.P. 192193 after recrystallization from ethanol.

EXAMPLE 17 Through the solution of 2.0 g. l-(4-fluoro-phenyl)-4- methylmercapto 2 phenyl 5,6,7,8 tetrahydro quinazolinium iodide in 300 ml. hot acetone, gaseous ammonia is bubbled through while the solution is refluxed for 2 hours. During the course of the reaction the evolution of methyl mercaptan can be detected. The solvent is removed under reduced pressure to yield the 1-(4-fluoro- 20 phenyl) 4 imino 2 phenyl 1,4,5,6,7,8 hexahydroquinazoline hydroiodide of the formula which melts after recrystallization from acetone at 288- 290.

EXAMPLE 18 According to the method described in Example 17, the following compounds are prepared from the same amount of the iodide mentioned and gaseous methylamine or ethylamine:

M.P. Recrystallized (deg) Irom-- 335-337 Methanol.

Compound 4-methylimino-1-(4fluoro-phenyl)-2- pl1eny11,4,5,6,7,Shexahydro-quinazoliue hydroiodide. 4-ethylimino-1-(4-fluoro-pheny1)-2-phenyl- 1,4,5,6,7,8-hexahydro-quinazoline hydroiodide.

121-123 Isopropanol.

EXAMPLE 19 To the solution of 1.0 g. 1-(4-fiuoro-phenyl)-4-methylmercapto 2 phenyl 5,6,7,8 tetrahydro quinazolinwhich melts after recrystallization from isopropanol at 127-1285".

21 EXAMPLE 20 Using in Example 19 instead of the n-propylamine the same amount of isopentylamine, 3-diethylamino-propylamine or 5 ml, n-butylamine, i-butylamine, tert. butylamine, n-pentylamine, n-hexylamine and 2-dimethylaminoor diethylamino-ethylamine, the following compounds are prepared:

M.P. Recrystallized (deg.) from- Compound 4-isopenty1imino-1-(4-fluoro-phenyl)- Isopropanol.

2-phenyl-1,4,5,6,7,8 hexahydroquinazoline hydroiodide. 4-(3-diethylamino-propyl-imino)-1- (4-fluoro-phenyl)-2-phenyl-1,4,5,6,7, S-hexahydro-quinazoline hydroiodide. 4-(Z-dirnethylaminoethylimino)-1-(4- fluorophenyl)-2-phenyl-1,4,5,6,7,8- hexahydro-quinazoline hydroiodide. 4-(2-diethylaminoethylimino)-1-(4- fiuoro-phenyl)-2-phenyl-1,4,5,6,7,8- hexahydro-quinazoline hydroiodide. 4n-butylimin0-1-(-fluoro-phenyl)-2 phenyl-l,4,5,6,7,8-hexahydro-quinazoliue hydroiodide. 4-i-buty1imino-1-(4-fluoro-phenyl)-2- phenyl-l,4,5,6,7,8-hexahydro-quinazoline hydroiodide. 4-tert. butylimino-l-(4-fiuoro-phenyl)- 2phenyl-1,4,5,6,7,8-hexahydro-quinazoline hydroiodide. 4-n-penty1imino-1-(4-fluoro-phenyD-2- phenyl-l,4,5,6,7,8-hexahydro-quinazoline hydroiodide. 4-n-hexylimino-1-(-fluoro-phenyl)-2- phenyl-1,4,5,6,7,8-hexahydro-quinazoline hydroiodide.

195497 Isopropauoldiethyl ether.

112-114 Ethanol.

193-195 Isopropanol.

202204 Isopropanoldiethyl ether.

218-220 Isopropanol.

The compounds of the invention described in Examples 17 to 19 in most instances show a double melting point, only one of which is indicated therein. For examle the 4 n pentylimino 1 (4 fiuoro phenyl) 2 phenyl- 1,4,5,6,7,8-hexahydro-quinazoline hydroiodide first melts at 102, resolidifies and again melts at 182,

22 What is claimed is: 1. A compound of the formula R1 I C C-Rz in which A stands for lower alkylene or lower alkenylene having from three to five carbon atoms as ring members and at most one double bond and each of the groups R and R stands for a member selected from the group consisting of alkyl having up to 12 carbon atoms, Ar-lower alkyl and Ar, wherein Ar is phenyl, (lower aIkyD-phenyl, (lower alkoxy)-phenyl, (halogeno)-phenyl, (lower alkylmercapto)-phenyl or (nitro)-phenyl.

2. A compound as claimed in claim 1, in which formula A stands for alkylene having from three to five carbon atoms, R stands for a member selected from the group consisting of alkyl having up to 12 carbon atoms, phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (halogeno)-phenyl, (lower alkyl-mercapto)-phenyl and (nitro)-phenyl, and R stands for a member selected from the group consisting of phenyl, (lower alkyl)- phenyl, (lower alkoxy)-phenyl, (halogen0)-phenyl, lower alkyl-mercapto)-phenyl and (nitro)-phenyl.

References Cited Albert et al.: Jour. Chem. Soc. (London), 1962, pp. 312930 Relied on.

Ziegenbein et al.: Angew Chem. vol. 71, p. 628 (1959).

Chemical Abstracts, vol. 64, Subject Index (P-Z) p. 29438 (1966).

HENRY R. JILES, Primary Examiner.

NATALIE TROUSOF, Assistant Examiner.

US. 01. X.R. 

